Process for preparing halogenated cyclopropane derivatives

ABSTRACT

A process for preparing compounds represented by the following general formula (I) wherein X represents chlorine atom or other and R represents alkoxy group, amino group or other, which comprises the step of allowing a compound represented by the formula: CH 2 ═CXF react with a compound represented by the formula: N 2 CHCOR in the presence of a catalyst containing a metal atom such as a transition metal of group 8 together with chiral carboxylic-type or amide-type ligands to preferentially obtain a stereoisomer of the compound of the general formula (I) wherein the stereochemical configuration at the 1-position is S-configuration

TECHNICAL FIELD

[0001] The present invention relates to a process for preparingoptically active halogenated cyclopropane derivatives which are usefulas synthetic intermediates for the preparation of synthetic newquinolone antibacterial agents having excellent activity and safety.

BACKGROUND ART

[0002] Among the new quinolone antibacterial agents having excellentantibacterial activity, synthetic antibacterial agents having afluorocyclopropyl group at the 1-position of the quinolone nucleus haveboth excellent antibacterial activity and safety, and accordingly, theyare expected as clinically useful drugs (Japanese Patent UnexaminedPublication (KOKAI) No. (Hei) 2-231475/1990). Optically active2-fluorocyclopropanecarboxylic acid and derivatives thereof having aspecific stereochemical configuration, i.e., (1S, 2S), are important assynthetic intermediates for these compounds,.

[0003] (1S,2S)-2-fluorocyclopropanecarboxylic acid is heretoforeprepared by the steps of addition of bromofluorocarbene to butadiene toproduce 1-bromo-1-fluoro-2-vinylcyclopropane; oxidation of the vinylgroup to obtain a carboxylic acid and then esterification and successivedebromination of the resulting product; separation of a cis-isomer fromthe resulting reaction mixture by distillation; hydrolysis of the estergroup of the cis-isomer to afford a carboxylic acid; and opticalresolution of the resulting carboxylic acid (see, the reaction schemeset out below).

[0004] Another method for preparing(1S,2S)-2-fluorocyclopropanecarboxylic acid is known which comprises thesteps of reacting a vinyl halogenide with a diazoacetic acid derivativein the presence of a variety of metal catalysts, optionally followed byadditional dehalogenation reaction, separation of stereoisomers, andoptical resolution (Japanese Patent Unexamined Publication (KOKAI) No.(Hei) 6-949911994 and Japanese Patent Unexamined Publication (KOKAI) No.(Hei) 5-194323/1993). However, no metal catalyst having one or morechiral ligands was used in the aforementioned processes.

[0005] These preparing processes involve the step of optical resolutionof the desired optically active compound having (1S,2S)-configurationafter the preparation of the racemic1,2-cis-2-fluorocyclopropanecarboxylic acid derivative, and the(1R,2R)-isomer, which comprises the half of the racemate, have to beremoved as waste matter. Therefore, these processes are not efficientfrom economical and industrial viewpoints.

[0006] The object of the present invention is to provide a efficient andconvenient process for preparing optically active halogenatedcyclopropane derivatives which are useful for the manufacture of theoptically active (1S,2S)-2-fluorocyclopropane-carboxylic acid orderivatives thereof. More specifically, the object of the presentinvention is to provide a process for preparing the aforementionedoptically active halogenated cyclopropane derivatives by astereoselective reaction using readily available starting materials.

DISCLOSURE OF THE INVENTION

[0007] The inventors of the present invention conducted various studiesto achieve the foregoing object, and as a result, they found that a2-fluoro-2-chlorocyclopropanecarboxylic acid derivative can be obtainedstereoselectively and in high yield by reacting a diazoacetic acidderivative with 1-fluoro-1-chloroethylene, for example, in the presenceof a metal catalyst having one or more chiral ligands. The inventors ofthe present invention also found that the optically active2-fluoro-cyclopropanecarboxylic acid derivatives having the desiredstereochemical configuration, i.e., (1S,2S), can be prepared in highyield by subjecting the aforementioned2-fluoro-2-chlorocyclopropanecarboxylic acid derivative todehalogenation reaction. The present invention was achieved on the basisof these findings.

[0008] The present invention thus provides a process for preparingcompounds represented by the following general formula (I):

[0009] wherein:

[0010] X represents chlorine atom, bromine atom, or iodine atom;

[0011] R represents a C₁₋₁₀ (containing 1-10 carbon atoms) alkyloxygroup which may have one or more halogen atoms or one or more C₁₋₁₀alkyloxy groups;

[0012] an aralkyloxy group constituted by an aryl group which may have asubstituent(s) and a C₁₋₁₀ alkyloxy group;

[0013] an aryloxy group having an aryl groups which may be substituted;

[0014] a C₁₋₁₀ alkylthio group which may have one or more halogen atoms;

[0015] an aralkylthio group constituted by an aryl group which may havea substituent(s) and a C₁₋₁₀ alkylthio group;

[0016] amino group; or

[0017] a substituted amino group which has one or more substituentsselected from the group consisting of a C₁₋₁₀ alkyl group, an aryl groupwhich may be substituted, an aralkyl group constituted by an aryl groupwhich may have a substituent(s) and a C₁₋₁₀ alkyl group, and an acylgroup;

[0018] provided that substituents of the substituted aryl groups areselected from the group consisting of a halogen atom, a C₁₋₁₀ alkylgroup, a C₁₋₁₀ halogenoalkyl group, a C₁₋₁₀ alkyloxy group, a carbamoylgroup which may be substituted, hydroxyl group, nitro group, cyanogroup, and an amino group which may be substituted,

[0019] characterized in that the process comprises the step of allowinga compound represented by the formula: N₂CHCOR wherein R is the same asthat defined above react with a compound represented by the formula:CH2═CXF wherein X is the same as that defined above in the presence of acatalyst comprising a metal atom selected from the group consisting of atransition metal of group 8, molybdenum, and copper, together with atleast one chiral ligand selected from the group consisting of acarboxylic acid-type ligand, an amide-type ligand, a phosphine-typeligand, an oxime-type ligand, a sulfonic acid-type ligand,1,3-diketone-type ligand, a Schiff base-type ligand, an oxazoline-typeligand, and a diamine-type ligand to preferentially produce astereoisomer of the compound of the general formula (I) wherein thestereochemical configuration at the I-position is S-configuration.

[0020] According to preferred embodiments of the above invention, thereare provided the aforementioned process which preferentially produces astereoisomer of a compound of the general formula (I) wherein thestereochemical configuration at the 1-position is S-configuration andthe substituent represented by —COR and the fluorine atom is incis-configuration; the aforementioned process which preferentiallyproduces a stereoisomer of the compound of the general formula (I)wherein the stereochemical configuration at the 1-position isS-configuration and the substituent represented by —COR and the fluorineatom is in trans-configuration; the aforementioned process wherein X ischlorine atom or bromine atom; the aforementioned process wherein R is aC₁₋₁₀ alkyloxy group; the aforementioned process wherein R is a C₁₋₆alkyloxy group; and the aforementioned process wherein R is ethoxygroup.

[0021] As preferred embodiments of the aforementioned invention, thereare also provided the aforementioned process which is carried out in thepresence of said catalyst containing at least one chiral ligand selectedfrom the group consisting of a carboxylic acid-type ligand and anamide-type ligand; the aforementioned process which is carried out inthe presence of a catalyst containing at least one chiral ligandselected from the group consisting of a carboxylic acid-type ligand andan amide-type ligand together with at least one ligand selected from thegroup consisting of a halogen-type ligand, a phosphine-type ligand, anoxime-type ligand, a sulfonic acid-type ligand, a 1,3-diketone-typeligand, a Schiff base-type ligand, and a carbon monoxide type ligand;the aforementioned process which is carried out in the presence of acatalyst containing at least one chiral ligand selected from the groupconsisting of a carboxylic acid-type ligand and an amide-type ligandtogether with at least one ligand selected from the group consisting ofa halogen-type ligand, a phosphine-type ligand, and a carbon monoxidetype ligand; and the aforementioned process which is carried out in thepresence of said catalyst containing at least one chiral ligand selectedfrom the group consisting of an oxazoline-type ligand and a diamine-typeligand.

[0022] As preferred embodiments of the aforementioned invention, thereare further provided the aforementioned process which is carried out inthe presence of the catalyst containing two or more identical chiralligands selected from the group consisting of a carboxylic acid-typeligand and an amide-type ligand; the aforementioned process which iscarried out in the presence of the catalyst containing the identicalchiral ligands selected from the group consisting of a carboxylicacid-type ligand and an amide-type ligand; the aforementioned processwhich is carried out in the presence of the catalyst containing at leastone carboxylic acid-type chiral ligand; the aforementioned process whichis carried out in the presence of the catalyst containing two or moreidentical carboxylic acid-type chiral ligands; the aforementionedprocess which is carried out in the presence of the catalyst containingas ligands only identical carboxylic acid-type optically active ligands;the aforementioned process which is carried out in the presence of thecatalyst containing at least one amide-type chiral ligand; theaforementioned process which is carried out in the presence of thecatalyst containing two or more identical amide-type chiral ligands; theaforementioned process which is carried out in the presence of thecatalyst containing as ligands only identical amide-type chiral ligands;the aforementioned process which is carried out in the presence of saidcatalyst containing cobalt, rhodium, iridium, ruthenium, palladium,molybdenum, copper, or iron as the metal atom; and the aforementionedprocess which is carried out in the presence of said catalyst containingrhodium as the metal atom. As preferred embodiments of theaforementioned invention, there are also provided the aforementionedprocess which is carried out in the presence of the catalyst containingat least one chiral ligand selected from the group consisting of anoxazoline-type ligand and a diamine-type ligand; the aforementionedprocess which is carried out in the presence of the catalyst containingcopper as the metal atom; and the aforementioned process wherein acopper source is at least one substance selected from the groupconsisting of copper (I) trifluoromethanesulfonate [CuOSO₂CF₃] andcopper (II) trifluoromethanesulfonate [Cu(OSO₂CF3)₂].

BEST MODE FOR CARRYING OUT THE INVENTION

[0023] The first embodiment of the process of the present invention ischaracterized in that, where a compound of the general formula (II)represented by CH₂═CXF and a compound of the general formula (III)represented by N₂CHCOR are reacted to give a compound of the generalformula (I), the process is carried out in the presence of theaforementioned specific catalyst to preferentially produce astereoisomer of the compound of the general formula (I) wherein thestereochemical configuration at the 1-position is S-configuration (inthe specification, among the carbon atoms constituting the cyclopropanering, the carbon atom to which the substituent —COR binds is referred toas the carbon atom at the 1-position).

[0024] One embodiment of the present invention is characterized in thata stereoisomer of the compound of the general formula (I) ispreferentially formed wherein the stereochemical configuration at the1-position is S-configuration and the substituent represented by —CORand the fluorine atom are in cis-configuration (the term“cis-configuration” herein used means that the substituent representedby —COR and the fluorine atom on the cyclopropane ring are present onthe same side of the plane provided by the cyclopropane ring). Anotherembodiment of the present invention is characterized in that astereoisomer of the compound of the general formula (I) ispreferentially formed wherein the stereochemical configuration at the1-position is S-configuration and the substituent represented by —CORand the fluorine atom are in trans-configuration.

[0025] In each of the inventions mentioned above, the wording “astereoisomer is preferentially formed” means that the produced amount ofthe desired stereoisomer as the target among the compounds of formula(I) exceeds those of the other stereoisomers. In the specification, thiswording should be construed in its broadest meaning, which includeswhere the produced amount of the desired stereoisomer only slightlyexceeds those of the other stereoisomers, and where only the desiredstereoisomer is substantially produced, but excludes where the producedamount of the desired stereoisomer is completely the same as those ofthe other stereoisomer.

[0026] In the compounds represented by the general formula (I) and thegeneral formula (II), X represents chlorine atom, bromine atom, oriodine atom. Among them, X may preferably be chlorine atom or bromineatom. As the compound of the above general formula (I),2-chloro-2-fluorocyclopropanecarboxylic acid derivatives and2-bromo-2-fluorocyclo-propanecarboxylic acid derivatives are preferred.

[0027] In the compounds of the general formula (I) and the generalformula (III), R represents a C₁₋₁₀ alkyloxy group (preferably a C₁₋₆alkyloxy group) which may have one or more halogen atoms or one or moreC₁₋₁₀ alkyloxy groups (preferably a C₁₋₆ alkyloxy group);

[0028] an aralkyloxy group constituted by an aryl group which may besubstituted and a C₁₋₁₀ alkyloxy group (preferably a C₁₋₆ alkyloxygroup);

[0029] an aryloxy group having one or more aryl groups which may besubstituted;

[0030] a C₁₋₁₀ alkylthio group (preferably a C₁₋₆ alkylthio group) whichmay have one or more halogen atoms;

[0031] an aralkylthio group constituted by an aryl group which may havea substituent(s) and a C₁₋₁₀ alkylthio group (preferably a C₁₋₆alkylthio group);

[0032] amino group; or

[0033] a substituted amino group which has one or two substituentsselected from the group consisting of a C₁₋₁₀ alkyl group (preferably aC₁₋₆ alkyl group), an aryl group which may be substituted, an aralkylgroup constituted by an aryl group which may be substituted togetherwith a C₁₋₁₀ alkyl group (preferably a C₁₋₆ alkyl group), and an acylgroup.

[0034] In the above definition, substituents of the substituted arylgroups are selected from the group consisting of a halogen atom, a C₁₋₁₀alkyl group (preferably a C₁₋₆ alkyl group), a C₁₋₁₀ halogenoalkyl group(preferably a C₁₋₆ halogenoalkyl group), a C₁₋₁₀ alkyloxy group(preferably a C₁₋₆ alkyloxy group), a carbamoyl group which may besubstituted, hydroxyl group, nitro group, cyano group, and an aminogroup which may be substituted.

[0035] In the above definition of R, the alkyloxy group may be astraight chain-, a branched chain-, or a cyclic alkyl. As the C₁₋₁₀alkyloxy group, for example, methoxy group, ethoxy group, n-propoxygroup, isopropoxy group, cyclopropoxy group, n-butoxy group, sec-butoxygroup, tert-butoxy group, cyclobutoxy group, n-pentoxy group, n-hexoxygroup, cyclohexyloxy group, levo-menthyloxy group or the like can beused. These C₁₋₁₀ alkyloxy groups may be substituted with one or morehalogen atoms (when the term “halogen atom” is herein referred to, theterm is used so as to include any of fluorine atom, chlorine atom,bromine atom, and iodine atom unless specifically indicated), or withone or more C₁₋₁₀ alkyloxy groups (for example, those exemplified above,preferably C₁₋₆ alkyloxy groups). As the alkyloxy group represented byR, a straight chain- or branched chain-C₁₋₆ alkyloxy group is preferred,and ethoxy group or methoxy group is particularly preferred.

[0036] The aralkyloxy group is constituted by an aryl group such asphenyl group and naphthyl group (which may be substituted) together withthe C₁₋₁₀ alkyloxy group mentioned above. Examples of the aralkyloxygroup include, for example, benzyloxy group, diphenylmethyloxy group,and triphenylmethyloxy group. When the aralkyloxy group has two or morearyl groups, those aryl groups may be identical or different. The arylgroup constituting the aryloxy group may be any one of aryl groups whichmay be substituted. For example, phenyl group or naphthyl group maysuitably used. Examples of the aryloxy group include, for example,phenoxy group, 1-naphthoxy group, and 2-naphthoxy group.

[0037] The C₁₋₁₀ alkylthio group and aralkylthio group correspond to theC₁₋₁₀ alkyloxy group and aralkyloxy group explained above, respectively,in which the oxygen atom constituting the oxy group is replaced with asulfur atom.

[0038] When R represents a substituted amino group, examples of a usablesubstituent on the amino group include a C₁₋₁₀ alkyl group, an arylgroup which may be substituted, an aralkyl group constituted by an arylgroup which may be substituted together with a C₁₋₁₀ alkyl group, and anacyl group. When two substituents bind to the amino group, they may bethe same or different.

[0039] With regard to the substituents on the amino group mentionedabove, the C₁₋₁₀ alkyl group may be any one of straight chain-, branchedchain-, or cyclic alkyl. For example, methyl group, ethyl group,n-propyl group, isopropyl group, cyclopropyl group, n-butyl group,sec-butyl group, tert-butyl group, cyclobutyl group, n-pentyl group,n-hexyl group, cyclohexyl group, or 1-menthyl group may be used. As thearyl group, phenyl group, naphthyl group, and the like can be used. Thearalkyl group is constituted by an aryl group such as phenyl group ornaphthyl group (which may be substituted) together with theaforementioned C₁₋₁₀ alkyl group. For example, benzyl group,diphenylmethyl group, triphenylmethyl group can be used. As the acylgroup, either of an aliphatic acyl group constituted by theaforementioned C₁₋₁₀ alkyl group together with carbonyl group, or anaromatic acyl group constituted by an aryl group which may besubstituted together with carbonyl group can be used. For example,acetyl group, benzoyl group and the like can be used.

[0040] With regard to the substituent explained above, a substituentselected from the group consisting of a halogen atom, the aforementionedC₁₋₁₀ alkyl group, a C₁₋₁₀ halogenoalkyl group being a C₁₋₁₀ alkyl groupsubstituted with one or more halogen atoms, the aforementioned C₁₋₁₀alkyloxy group, a carbamoyl group which may be substituted, hydroxylgroup, nitro group, cyano group, and an amino group which may besubstituted can be used as the substituent of the substituted arylgroup. When the aryl group has two or more substituents, thosesubstituents may be the same or different. When a substituted aminogroup and/or a substituted carbamoyl group is used as one or moresubstituents on the aryl group, the substituents on the amino group,those explained above as to the definition wherein R is a substitutedamino group, may be used as substituents on the amino group and/or thecarbamoyl group.

[0041] The process of the present invention is characterized in that theprocess utilizes a catalyst containing a metal atom selected from thegroup consisting of a transition metal of group 8, molybdenum, andcopper, together with at least one chiral ligand selected from the groupconsisting of a carboxylic acid-type ligand, an amide-type ligand, aphosphine-type ligand, an oxime-type ligand, a sulfonic acid-typeligand, a 1,3-diketone-type ligand, a Schiff base-type ligand, anoxazoline-type ligand, and a diamine type ligand for the reaction of acompound of the formula (II) and a compound of the formula (III). As tothe ligand of the catalyst, the ligand is specified in the specificationbased on the type of a functional group coordinating to the metal atomof the catalyst. For example, when carboxyl group in a ligandcoordinates to a metal atom, the ligand is referred to as a carboxylicacid-type ligand. However, where a carboxylic acid ligand, for example,is referred to in the specification, one or more functional groups otherthan carboxyl group (e.g., one or more functional groups such as analkyl group, an aryl group, an aralkyl group, and a heterocyclic group)may be present in the ligand. As to an amide-type ligand, aphosphine-type ligand, an oxime-type ligand, a sulfonic acid-typeligand, a 1,3-diketone-type ligand, a Schiff base-type ligand, anoxazoline-type ligand, and a diamine-type ligand, the wording should beinterpreted similarly.

[0042] Among the catalysts comprising the aforementioned components, forexample, the following catalysts are preferably used for the process ofthe present invention:

[0043] (a) the aforementioned catalyst which contains at least onechiral ligand which is selected from the group consisting of acarboxylic acid-type ligand and an amide-type ligand;

[0044] (b) the catalyst which contains at least one chiral ligandselected from the group consisting of a carboxylic acid-type ligand andan amide-type ligand, together with at least one ligand which isselected from the group consisting of a halogen-type ligand, aphosphine-type ligand, an oxime-type ligand, a sulfonic acid-typeligand, a 1,3-diketone-type ligand, a Schiff base-type ligand, and acarbon monoxide-type ligand;

[0045] (c) the catalyst which contains at least one chiral ligand whichis selected from the group consisting of a carboxylic acid-type ligandand an amide-type ligand, together with at least one ligand selectedfrom the group consisting of a halogen-type ligand, a phosphine-typeligand, and a carbon monoxide-type ligand;

[0046] (d) the catalyst which contains at least one chiral ligand whichis selected from the group consisting of an oxazoline-type ligand and adiamine-type ligand; and the like.

[0047] Iron, nickel, rhodium, palladium, cobalt, iridium, ruthenium, andthe like may preferably be used as the transition metal of group 8, andas a metal other than the transition metals of group 8, molybdenum orcopper can be used. It is preferred that the valence of these metalatoms are divalent at forming the catalyst. Where a metal such as copperis used, the metal may be monovalent. Examples of preferred metal atomsinclude, for example, rhodium, palladium, cobalt, iridium, ruthenium,molybdenum, copper, and iron.

[0048] The catalyst used for the process of the present invention ischaracterized in that it contains at least one chiral ligand. The chiralligand is selected from the group consisting of a carboxylic acid-typeligand, an amide-type ligand, a phosphine-type ligand, an oxime-typeligand, a sulfonic acid-type ligand, a 1,3-diketone-type ligand, aSchiff base-type ligand, an oxazoline-type ligand, and a diamine-typeligand, and preferably, the ligand is selected from the group consistingof a carboxylic acid-type ligand, an amide-type ligand, anoxazoline-type ligand, and a diamine-type ligand. When two or morechiral ligands coordinate to the aforementioned metal, it is preferablethat each of the chiral ligands is structurally and optically identical.However, two or more different types of optically active ligands maycoordinate to the metal.

[0049] For example, all of the ligands on the aforementioned metal maybe chiral ligands selected from a carboxylic acid-type ligand and anamide-type ligand. Alternatively, for example, one or more chiralligands among the ligands on the metal may be selected from the groupconsisting of a carboxylic acid-type ligand and an amide-type ligand,and the other one or more ligands may be selected from the groupconsisting of a halogen-type ligand, a phosphine-type ligand, anoxime-type ligand, a sulfonic acid-type ligand, a 1,3-diketone-typeligand, a Schiff base-type ligand, and a carbon monoxide-type ligand,preferably from the group consisting of a halogen-type ligand, aphosphine-type ligand, and a carbon monoxide-type ligand. In this case,the aforementioned ligands other than the carboxylic acid and the amidetypes may be chiral ligands.

[0050] As a compound for providing the chiral carboxylic acid-typeligand, for example, optically active amino acids or optically activecarboxylic acids having one or more asymmetric carbons can be used. Asthe optically active amino acids, for example, D- or L- alanine,arginine, asparagine, aspartic acid, cysteine, cystine, histidine,hydroxylysine, hydroxyproline, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, thyroxine, tryptophane,tyrosine, valine, aminobutyric acid, citrulline, cystathionine,phenylglycine, methionine, norleucine, norvaline, glutamic acid,glutamine, penicillamine, pipecolic acid, 3,5-dibromotyrosine,3,5-diiodotyrosine and other may be used.

[0051] As the optically active carboxylic acids, for example,2-chloropropionic acid, 2-bromopropionic acid, 2-acetoxypropionic acid,2,3-diaminopropionic acid, 2-phenylpropionic acid,2-chloro-3-phenylpropionic acid, 2-hydroxy-3-phenylpropionic acid,2-(6-methoxy-2-naphthyl)propionic acid, 3-acetylthio-2-methylpropionicacid, 2-amino-3-guanidinopropionic acid, 3-acetylthioisobutyric acid,2-chlorobutyric acid, 2-chloro-3-methylbutyric acid, 3-hydroxybutyricacid, 2,4-diaminobutyric acid, 2-methylbutyric acid, 2-phenylbutyricacid, 3-phenylbutyric acid, 2-chloro-3-methylvaleric acid,2-chloro-4-methylvaleric acid, menthoxyacetic acid,2-methoxyphenylacetic acid, 2-methoxy-2-trifluoromethylphenylaceticacid, phenylsuccinic acid, shikimic acid, camphoric acid, mandelic acid,hexahydromandelic acid, monomenthyl phthalate,N-(α-methylbenzyl)phthalic acid monoamide,2-oxothiazolidine-4-carboxylic acid, 3-phenyllactic acid, lactic acid,4-hydroxypyrroline, pyroglutamic acid, malic acid, 2-methylmalic acid,2-benzamidecyclohexanecarboxylic acid, 3-methyladipic acid, tartaricacid and other may be used.

[0052] Among functional groups existing in the chiral amino acids or thechiral carboxylic acids mentioned above, functional groups other thanthe carboxyl group for coordinating to the metal atom (e.g., aminogroup) may be protected by means of a protective group available tothose skilled in the art. As protective groups for amino group, forexample, maleic anhydride, 2,3-dichloromaleic anhydride, phthalicanhydride, 3,6-dichlorophthalic anhydride, 4,5-dichlorophthalicanhydride, 3,6-difluorophthalic anhydride, 4,5- difluorophthalicanhydride, 3,4,5,6-tetrachlorophthalic anhydride,3,4,5,6-tetrafluorophthalic anhydride, hexahydrophthalic anhydride,1,2,3,6-tetrahydrophthalic anhydride, glutaric anhydride,3-methylglutaric anhydride, itaconic anhydride, 1,8-naphthalicanhydride, succinic anhydride, tetrafluorosuccinic anhydride,3,4,5,6-tetrahydrosuccinic anhydride, citraconic anhydride,1-cyclopentene-1,2-dicarboxylic anhydride,cis-endo-5-norbornene-2,3-dicarboxylic anhydride,bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride, formyl group,acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonylgroup, methoxycarbonyl group, tert-butoxycarbonyl group,trifluoromethanesulfonyl group, p-toluenesulfonyl group and other may beused.

[0053] As a compound for providing the optically active amide-typeligand, examples include 3-acetamidopyrrolidine,1-benzoyl-2-tert-butyl-3-methyl-4-imidazolidinone,1-tert-butoxycarbonyl-2-tert-butyl-3-methyl-4-imidazolidinone,4-amino-3-isoxazolidone, 1,5-dimethyl-4-phenyl-2-imidazolidinone,N-(3,5-dinitrobenzoyl)-1-phenylethylamine,5-(hydroxymethyl)-2-pyrrolidinone, 4-isopropyl-2-oxazolizinone,4-methyl-5-phenyl-2-oxazolizinone, 2-oxothiazolidine-4-carboxylic acid,4-phenyloxazolidin-2-one, prolineamide, proline-2-naphthylamide,pyroglutamic acid ethyl ester, pyroglutamic acid 2-naphthylamide andother.

[0054] As a compound for providing the chiral oxazoline-type ligand, forexample, an example includes the compounds set out below:

[0055] wherein R¹ represents a lower alkyl group having 1 to 5 carbonatoms or a phenyl group which may be substituted, and R² representshydrogen atom or methyl group.

[0056] As specific compounds for providing the chiral oxazoline-typeligand, examples include2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline],2,2′-isopropylidene-bis-[(4S)-4-tert-butyl-2-oxazoline],2,2′-methylenebis[(4S)-4-isopropyl-2-oxazoline],2,2′-isopropylidenebis[(4S)-4-isopropyl-2-oxazoline],2,2′-isopropylidenebis[(4S)-4-benzyl-2-oxazoline] and other.

[0057] As a compound for providing the chiral diamine-type ligand, anexample includes the compounds set out below:

[0058] wherein R³ represents benzyl group, 2,4,6-trimethylphenylmethylgroup, or diphenyl-methyl group.

[0059] As specific compounds for providing the chiral diamine-typeligand, examples include(1R,2R)-1,2-diphenyl-N,N′-bis[2,4,6-trimethylphenylmethyl]-ethylenediamine,(1R,2R)-1,2-diphenyl-N,N′-bisbenzylethylenediamine and other.

[0060] The halogen type-ligand, the phosphine-type ligand, theoxime-type ligand, the sulfonic acid-type ligand, the 1,3-diketone-typeligand, the Schiff basetype ligand, and the carbon monoxide-type ligandare well-known to those skilled in the art and can be appropriatelychosen.

[0061] As examples of the catalyst preferably used for the process ofthe present invention, catalysts comprising divalent rhodium togetherwith chiral carboxylic acid-type ligands are shown below. However, thecatalysts used for the process of the present invention are not limitedto those indicated below.

[0062] As other examples of the catalyst preferably used for the processof the present invention, catalysts having chiral amide-type ligands areshown below. However, the catalysts used for the process of the presentinvention are not limited to those set out below.

[0063] Those catalysts mentioned above can be prepared by, for example,a method comprising the steps of adding rhodium (II) acetate dimer andan excess amount of a carboxylic acid or an amide compound tochlorobenzene, and refluxing the mixture and then purifying the product(Callot, H. J. and Mets, F., Tetrahedron, 41, 4495, 1985). They can alsobe produced by refluxing a mixture of rhodium (II) chloride trihydrate,carboxylic acid compound, and sodium hydrogencarbonate in anhydrousethanol under inert atmosphere, and then purifying the product(Demoncean, A., et al., Tetrahedron, 46, 3889, 1990). However, thecatalysts used for the process of the present invention are not limitedto those produced by the aforementioned preparing methods. It can bereadily understood that the aforementioned catalysts can also beappropriately prepared by suitably altering or modifying the reactionconditions, reagents or other specified for the methods disclosed in theliteratures.

[0064] Among the catalysts suitably used for the present invention,examples of catalysts containing one or more oxazoline-type ligands ordiamine-type ligands together with copper include, for example, acatalyst obtainable from2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] and copper (I)trifluoromethane-sulfonate; a catalyst obtainable from2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] and copper (II)trifluoromethane-sulfonate; a catalyst obtainable from2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline], copper (II)trifluoromethanesulfonate and phenylhydrazine; a catalyst obtainablefrom 2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline] and copper (II)trifluoromethanesulfonate; a catalyst obtainable from(1R,2R)-1,2-diphenyl-N,N′-bis[2,4,6-trimethylphenylmethyl]-ethylenediamine,copper (II) trifluoromethanesulfonate and phenylhydrazine and other.However, the catalysts used for the process of the present invention arenot limited to those mentioned above.

[0065] For example, the process of the present invention can be carriedout as explained below. The diazoacetic acid derivatives represented bythe formula (III) can be prepared by a method well-known to thoseskilled in the art. For example, a diazoacetic acid ester anddiazoacetic acid amide can be easily produced by subjecting respectivecorresponding compounds having an amino group to diazotization reaction.The 1-fluoro-1-haloethylenes represented by the formula (II) aregenerally of a lower boiling point, and they can be used afterliquefaction at a low temperature or dissolution in an organic solvent.They can also be used under elevated pressure as required. For thereaction, examples of an applicable process include a process comprisingthe steps of adding a necessary amount of the aforementioned catalyst toan ethylene compound of the formula (II) or its solution, and thenadding a compound of the formula (III) to the mixture; or a processcomprising the steps of adding a compound of the formula (III) to anethylene compound of the formula (II) or its solution, and then adding anecessary amount of the aforementioned catalyst to the mixture.

[0066] The above reaction can be carried out in the presence or absenceof a solvent. When a solvent is used, types of the solvent are notlimited so long as they, per se, are inert in the reaction. For example,aprotic solvents can be used, and preferably, aliphatic hydrocarbons,halogenated hydrocarbons, ethers and other can be used. Morespecifically, aliphatic hydrocarbons such as n-hexane, n-heptane, andcyclohexane; halogenated hydrocarbons such as dichloromethane and1,2-dichloroethane; and ethers such as diethyl ether and tetrahydrofurancan be used. Among them, dichloromethane, n-heptane, or cyclohexane ismost generally used.

[0067] Amount of the catalyst is not particularly limited. In general,the amount can be suitably chosen within a range of a so-calledcatalytic amount. For example, the aforementioned catalyst can be usedin a molar amount of about 10% or less based on the molar amount of thecompound of the general formula (III), preferably in a molar amountwithin a range of around 0.01-10%. The reaction may be carried out undercooling, at room temperature, or under warming. For example, thereaction may be carried out at a temperature in a range of from about−100° C. to 100° C., preferably from about −50° C. to 50° C. Reactiontime may generally be in a range of from about 30 minutes to about 48hours, usually in a range of from about 1 hour to 24 hours. The reactionmay be carried out under elevated pressure by using a sealed vessel suchas an autoclave.

[0068] According to the aforementioned process of the present invention,either a stereoisomer wherein the stereochemical configuration at the1-position is S-configuration and the substituent represented by —CORand the fluorine atom are in cis-configuration, or a stereoisomerwherein the stereochemical configuration at the 1-position isS-configuration and the substituent represented by —COR and the fluorineatom are in trans-configuration can be preferentially prepared bysuitably choosing the type of the catalyst used or other conditions.Those skilled in the art will readily understand that they canappropriately choose such catalyst by referring to the presentspecification.

[0069] A stereoisomer of a compound of the general formula (I) producedaccording to the aforementioned process of the present invention can bereadily converted into a 2-fluorocyclopropanecarboxylic acid derivativeby subjecting the stereoisomer to dehalogenation reaction (as to thisreaction, fluorine atom is excluded from “halogen”) to replace thesubstituent X with hydrogen atom. Therefore, according to furtherembodiments of the present invention, there are provided a process forpreparing (1S,2S)-2-fluorocyclopropanecarboxylic acid derivatives whichcomprises the steps of preparing a stereoisomer of the compound of thegeneral formula (I) according to the aforementioned process; and thensubjecting the resulting stereoisomer to dehalogenation to prepare a(1S,2S)-2-fluorocyclopropanecarboxylic acid derivative; and a processfor preparing (1S,2S)-2-fluorocyclopropanecarboxylic acid derivativeswhich comprises the step of subjecting a stereoisomer of the compound ofthe general formula (I) prepared according to the aforementionedreaction to dehalogenation reaction without isolation or purification.

[0070] When the stereoisomer wherein the stereochemical configuration atthe 1-position is S-configuration and the substituent represented by—COR and the fluorine atom is in cis-configuration is produced accordingto the process of the present invention,(1S,2S)-2-fluorocyclopropanecarboxylic acid can be prepared by carryingout a retention reaction as the dehalogenation reaction. On the otherhand, when the stereoisomer wherein the stereochemical configuration atthe 1-position is S-configuration and the substituent represented by—COR and the fluorine atom is in trans-configuration is producedaccording to the process of the present invention,(1S,2S)-2-fluorocyclopropanecarboxylic acid can be prepared by carryingout an inversion reaction as the dehalogenation reaction.

[0071] Methods for the dehalogenation are not particularly limited. Forexample, hydrogenolysis by using Raney nickel catalyst in the presenceof hydrogen gas flow and a base is preferable (Japanese PatentUnexamined Publication (KOKAI) No. (Hei) 7-97353/1995). Thisdehalogenation proceeds as retention of configuration, and accordingly,it is preferred to employ this dehalogenation when the stereoisomer ofthe compound of the general formula (I) wherein the stereochemicalconfiguration at the 1-position is S-configuration and the substituentrepresented by —COR and the fluorine atom is in cis-configuration isproduced according to the process of the present invention.

[0072] Optical purity of the resulting 2-fluorocyclopropanecarboxylicacid derivative can be readily determined by means of, for example, agas chromatographic analysis using an optically active capillary columnafter the 2-fluorocyclopropanecarboxylic acid derivative is convertedinto an ester compound. Alternatively, a liquid chromatographic analysismay also be applicable after the 2-fluorocyclopropanecarboxylic acidderivative is converted into an optically active amide compound such asa 1-phenylethylamide derivative.

EXAMPLES

[0073] The present invention will be explained more specifically byreferring to the following examples. However, the scope of the presentinvention is not limited to these examples.

Example 1 (1S,2S)-2-Fluorocyclopropanecarboxylic Acid Ethyl Ester

[0074] Dichloromethane (10 ml) was charged in a two-neck flask andcooled to about −60° C., and then was bubbled 1-chloro-1-fluoroethylenetill 4.5 g of the gas was dissolved. This solution was added withdirhodium (II) tetrakis(N-(3,6-dichlorophthaloyl)-L-phenylalanine) (84mg), and then the reaction mixture was cooled to be kept at −40° C.Ethyl diazoacetate (corresponding to 5 mmol) was dissolved indichloromethane, and then the resulting solution was cooled with dryice/acetone and added dropwise to the aforementioned reaction mixtureover 30 minutes. After the dropwise addition was completed, the reactionmixture was analyzed by gas chromatography to find that2-chloro-2-fluorocyclopropanecarboxylic acid ethyl ester was formed in a86% yield and the produced ratio of the cis-isomer and the trans-isomerwas 1.46:1.

[0075] Physicochemical properties of these products were as follows:

[0076]¹H-NMR 400 MHz (CDCl₃) δppm:

[0077] Cis-isomer: 1.30 (3H, t, J=7.3 Hz), 1.69 (1H, td, J=7.3, 9.3Hz),2.24 (1H, td, J=7.8 16.1 Hz), 2.38 (1H, ddd, J=1.0, 7.8, 10. 0 Hz), 4.22(2H, q, J=7.3 Hz)

[0078] Trans-isomer: 1.31 (3H, t, J=7.3 Hz), 1.83-1.94 (2H, m), 2.54(1H,m), 4.23 (2H, q, J=7.3 Hz)

[0079] Retention times observed by gas chromatographic analysis [column:TC-WAX (GLSciences) 30 m×0.25 mm ø, column temperature: 70° C., injectortemperature:

[0080] 200° C., detector temperature: 200° C., carrier gas: helium]:

[0081] Cis-isomer: 6.7 minutes

[0082] Trans-isomer: 6.2 minutes

[0083] The resulting ethyl 2-chloro-2-fluorocyclopropanecarboxylate wascharged into an autoclave, and added with Raney nickel (0.5 ml) andethanol (5 ml). The mixture was further added with 1,2-diaminoethane(0.54 g) and stirred at room temperature under hydrogen atmosphere at 50Kgf/cm² for 24 hours. After the completion of the reaction, Raney nickelwas removed by filtration, and then the resulting reaction mixture wasanalyzed by gas chromatography to find that ethyl2-fluorocyclopropanecarboxylate was formed quantitatively and theoptical purity of ethyl (1S,2S)-2-fluorocyclopropanecarboxylate was 21%e.e.

[0084] Analytical data of the products were as follows:

[0085]¹H-NMR 400 MHz (CDCl₁₃) δppm:

[0086] Cis-isomer: 1.11-1.18 (1H, m), 1.29 (3H, t, J=7.1 Hz), 1.75-1.84(2H, m), 4.20 (2H, q, J=7.1 Hz), 4.73 (1H, dm, J=65.1 Hz)

[0087] Trans-isomer: 1.24-1.34 (1H, m), 1.27 (3H, t, J=7.1 Hz),1.41-1.49 (1H, m), 2.04-2.11 (1H, -m), 4.14 (2H, q, J=7.1 Hz), 4.80 (1H,dm, J=63.5 Hz)

[0088] Retention times observed by gas chromatographic analysis [column:CP-Cyclodex- β-236M 25 m×0.25 mm ø, column temperature: 75° C., injectortemperature: 200° C., detector temperature: 200° C., carrier gas:helium]:

[0089] Ethyl (1S,2S)-2-fluorocyclopropanecarboxylate: 9.8 minutes

[0090] Ethyl (1R,2R)-2-fluorocyclopropanecarboxylate: 9.4 minutes

Example 2 (1S,2S)-2-Fluorocyclopropanecarboxylic Acid Ethyl Ester

[0091] In a similar manner to that of Example 1,tetrakis(N-benzyloxycarbonyl-L-proline) dirhodium (II) (30 mg) was addedto a solution of 1-chloro-1-fluoroethylene (3.7 g) in dichloromethane (5ml). A chilled solution of dichloromethane containing ethyl diazoacetate(corresponding to 2.5 mmol) was added dropwise to the solution overabout 30 minutes. After the completion of the dropwise addition, thereaction mixture was analyzed by gas chromatography to find that ethyl2-chloro-2-fluorocyclopropanecarboxylate was formed in a 73% yield andthe produced ratio of the cis-isomer and the trans-isomer was 1.39:1.The resulting ethyl 2-chloro-2-fluorocyclopropanecarboxylate wasconverted into ethyl 2-fluorocyclopropanecarboxylate in a similar mannerto that of Example 1. The conversion ratio of the reaction was found tobe 100%, and the optical purity of ethyl(1S,2S)-2-fluorocyclopropanecarboxylate was 19% e.e.

Example 3 (1S,2S)-2-Fluorocyclopropanecarboxylic Acid Ethyl Ester

[0092] In a similar manner to that of Example 1,tetrakis[(-)-cis-2-benzamidecyclohexanecarboxylate] dirhodium (II) (60mg) was added to a solution of 1-chloro-1-fluoroethylene (7.7 g) indichloromethane (10 ml). A chilled dichloromethane solution containingethyl diazoacetate (corresponding to 5 mmol) was added dropwise to thesolution over about 30 minutes. After the dropwise addition wascompleted, the reaction mixture was analyzed by gas chromatography tofind that ethyl 2-chloro-2-fluorocyclopropanecarboxylate was formed in a71% yield and the produced ratio of the cis-isomer and the trans-isomerwas 1.25:1. The resulting ethyl 2-chloro-2-fluorocyclopropanecarboxylatewas converted into ethyl 2-fluorocyclopropane-carboxylate in a similarmanner to that of Example 1. The conversion ratio of the reaction wasfound to be 100%, and the optical purity of ethyl(1S,2S)-2-fluorocyclopropanecarboxylate was 18% e.e.

Example 4 Ethyl 2-chloro-2-fluorocyclopropanecarboxylate

[0093] Cyclohexane (76.6 g),2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (64.8 mg, 0.22mmol), and copper (II) trifluoromethanesulfonate (72.1 mg, 0.20 mmol)were charged in an autoclave, and then 1-chloro-1-fluoroethylene (76.8g, 0.95 mol) was charged under elevated pressure. After the mixedsolution was cooled to 10° C., a mixed solution containing 95% of ethyldiazoacetate (12.0 g, 100 mmol) and cyclohexane (50 g) was charged underelevated pressure over five hours. Cyclohexane (20 ml) was furthercharged under elevated pressure and stirring was continued at the sametemperature for 1 hour, and then the internal pressure was released togive a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate incyclohexane (179.3 g). This solution was analyzed by gas chromatographyto find that the content of the ethyl2-chloro-2-fluorocyclopropanecarboxylate was 6.52% (yield based on ethyldiazoacetate: 70.1%), and the ratio of cis-isomer/trans-isomer was64.4/35.6.

[0094] After the cyclohexane was evaporated under reduced pressure froma part of the resulting reaction mixture, ethyl2-chloro-2-fluorocyclopropanecarboxylate was obtained by distillationunder reduced pressure at 20 mmHg. The product was analyzed by gaschromatography to find that the optical purity of the cis-isomer was 99%e.e. (1S,2R), and the optical purity of the trans-isomer was 91% e.e.(1S,2S). Retention times observed by gas chromatographic analysis[content analysis and cis/trans ratio analysis; column: HR-20M (ShinwaKako), 0.25 mm ø×30 m, column temperature: 50° C. (0 minute)→+5°C./minute→200° C. (0 minute), injector temperature: 200° C., detectortemperature: 250° C., carrier gas: helium, 65 ml/minute, split ratio:1:50]:

[0095] Cis-isomer: 15.0 minutes

[0096] Trans-isomer: 14.6 minutes

[0097] Retention times observed by gas chromatographic analysis[analysis of the optically active compounds; column:CP-Cyclodextrine-β-236M-19 (Chromatopack), 0.25 mm ø×50 m, columntemperature: 85° C. (20 minutes)→+10° C./minute→200° C. (10 minutes),injector temperature: 250° C., detector temperature: 250° C., carriergas: helium 70 ml/minute, split ratio: 1:100]:

[0098] (1R,2R)-Isomer: 21.7 minutes

[0099] (1S,2S)-Isomer+(1R,2S)-isomer: 21.9 minutes

[0100] (1S,2R)-Isomer: 22.2 minutes

Example 5 Ethyl 2-chloro-2-fluorocyclopropanecarboxylate

[0101] Cyclohexane (76.6 g),2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (75.8 mg, 0.26mmol), and copper (I) trifluoromethanesulfonate benzene complex (58.3mg, 0.23 mmol) were added in an autoclave, and then1-chloro-1-fluoroethylene (78.9 g, 0.98 mol) was charged under elevatedpressure. After the mixed solution was cooled to 10° C., the a mixedsolution containing 95% of ethyl diazoacetate (12.0 g, 100 mmol) andcyclohexane (50 g) was charged into the autoclave under elevatedpressure over five hours. Cyclohexane (20 ml) was further charged underelevated pressure and stirring was continued at the same temperature for1 hour, and then the internal pressure was released to give a solutionof ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (170.0g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylatewas 6.45% (yield based on ethyl diazoacetate: 65.6%), and the ratio ofcis-isomer/trans-isomer was 64.6/35.4. The optical purity of thecis-isomer was 99% e.e. (1S,2R), and the optical purity of thetrans-isomer was 92% e.e. (1S,2S).

Example 6 Ethyl 2-chloro-2-fluorocyclopropanecarboxylate

[0102] Cyclohexane (76.6 g),2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (500 mg, 1.7mmol), and copper (II) trifluoromethanesulfonate (360 mg, 1.0 mmol) wereadded in an autoclave, and the mixture was cooled to a temperature below−30° C., and then 1-chloro-1-fluoroethylene (80 g, 1.0 mol) was chargedunder elevated pressure. Phenylhydrazine (0.11 g, 1.0 mmol) was added tothis mixture under elevated pressure, and then temperature was raised to30° C. Then, a mixed solution containing 97.6% of ethyl diazoacetate(11.69 g, 100 mmol) and cyclohexane (50 g) was charged under elevatedpressure over five hours. Cyclohexane (20 ml) was further charged underelevated pressure and stirring was continued at the same temperature for1 hour, and then the internal pressure was released to give a solutionof ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (166.7g). The content of was 3.95% (yield based on ethyl diazoacetate: 39.5%),and the ratio of cis-isomer/trans-isomer was 65.0/35.0. The opticalpurity of the cis-isomer was 98% e.e. (1S,2R) or more, and the opticalpurity of the trans-isomer was 94% e.e. (1S,2S).

Example 7 Ethyl 2-chloro-2-fluorocyclopropanecarboxylate

[0103] n-Heptane (38.3 g),2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (162 mg, 0.55mmol), and copper (II) trifluoromethanesulfonate (180 mg, 0.50 mmol)were added in in an autoclave, and then 1-chloro-1-fluoroethylene (40 g,0.50 mol) was charged under elevated pressure. After the mixed solutionwas warmed to 30° C., a mixed solution containing 95% of ethyldiazoacetate (6.0 g, 50 mmol) and n-heptane (25 g) was charged underelevated pressure over five hours. n-Heptane (20 ml) was further chargedunder elevated pressure and stirring was continued at the sametemperature for 1 hour, and then the internal pressure was released toobtain a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate inn-heptane (90.0 g). The content of the ethyl2-chloro-2-fluorocyclopropanecarboxylate was 3.73% (yield based on ethyldiazoacetate: 40.3%), and the ratio of cis-isomer/trans-isomer was64.0/36.0. The optical purity of the cis-isomer was 98% e.e. (1S,2R),and the optical purity of the trans-isomer was 86% e.e. (1S,2S).

Example 8 Ethyl 2-chloro-2-fluorocyclopropanecarboxylate

[0104] Cyclohexane (76.6 g),2,2′-methylenebis[(4S)-4-tert-butyl-2-oxazoline] (293 mg, 1.1 mmol), andcopper (II) trifluoromethanesulfonate (361 mg, 1.0 mmol) were added inan autoclave, and then 1-chloro-1-fluoroethylene (80 g, 1.0 mol) wascharged under elevated pressure. After the mixture was warmed to 30° C.,a mixed solution containing 95% of ethyl diazoacetate (12.01 g, 100mmol) and cyclohexane (50 g) was charged under elevated pressure overfive hours. Cyclohexane (20 ml) was further charged under elevatedpressure and stirring was continued at the same temperature for 1 hour,and then the internal pressure was released to obtain a solution ofethyl 2-chloro-2-fluorocyclopropane-carboxylate in cyclohexane (183.86g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylatewas 4.92% (yield based on ethyl diazoacetate: 54.3%), and the ratio ofcis-isomer/trans-isomer was 59.5/40.5. The optical purity of thecis-isomer was 71% e.e. (1S,2R), and the optical purity of thetrans-isomer was 19% e.e. (1S,2S).

Example 9 Ethyl 2-chloro-2-fluorocyclopropanecarboxylate

[0105] Dichloromethane (38 g),(1R,2R)-1,2-diphenyl-N,N′-bis[2,4,6-trimethylphenyl-methyl]ethylenediamine(715 mg, 1.5 mmol), and copper (II) trifluoromethanesulfonate (180 mg,0.5 mmol) were added in an autoclave, and then 1-chloro-1-fluoroethylene(40 g, 500 mmol) was charged under elevated pressure. After the mixturewas warmed to 30° C., a mixed solution containing 95% of ethyldiazoacetate (6.00 g, 50 mmol) and dichloromethane (50 ml) was chargedunder elevated pressure over five hours. Dichloromethane (20 ml) wasfurther charged under elevated pressure and stirring was continued atthe same temperature for 1 hour, and then the internal pressure wasreleased to obtain and a solution of ethyl2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (106.31 g). Thecontent of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 3.62%(yield based on ethyl diazoacetate: 46.2%), and the ratio ofcis-isomer/trans-isomer was 62.4/37.6. The optical purity of thecis-isomer was 75% e.e. (1S,2R), and the optical purity of thetrans-isomer was 73% e.e. (1S,2S).

Industrial Applicability

[0106] According to the process of the present invention, opticallyactive halogenated cyclopropane derivatives which are useful for themanufacture of the optically active(1S,2S)-2-fluorocyclopropanecarboxylic acid can be efficiently andstereoselectively prepared.

What is claimed is:
 1. A process for preparing compounds represented bythe following general formula (I):

wherein: X represents chlorine atom, bromine atom, or iodine atom; Rrepresents a C₁₋₁₀ (containing 1-10 carbon atoms) alkyloxy group whichmay have one or more halogen atoms or C₁₋₁₀ alkyloxy groups; anaralkyloxy group constituted by an aryl group which may have asubstituent(s) and a C₁₋₁₀ alkyloxy group; an aryloxy group having anaryl groups which may be substituted; a C₁₋₁₀ alkylthio group which mayhave one or more halogen atoms; an aralkylthio group constituted by anaryl group which may have a substituent(s) and a C₁₋₁₀ alkylthio group;amino group; or a substituted amino group which has one or moresubstituents selected from the group consisting of a C₁₋₁₀ alkyl group,an aryl group which may be substituted, an aralkyl group constituted byan aryl group which have a substituent(s) and a C₁₋₁₀ alkyl group, andan acyl group; provided that substituents of the substituted aryl groupsare selected from the group consisting of a halogen atom, a C₁₋₁₀ alkylgroup, a C₁₋₁₀ halogenoalkyl group, a C₁₋₁₀ alkyloxy group, a carbamoylgroup which may be substituted, hydroxyl group, nitro group, cyanogroup, and an amino group which may be substituted, characterized inthat the process comprises the step of allowing a compound representedby the formula: N₂CHCOR wherein R is the same as that defined abovereact with a compound represented by the formula: CH₂═CXF wherein X isthe same as that defined above in the presence of a catalyst comprisinga metal atom selected from the group consisting of a transition metal ofgroup 8, molybdenum, and copper, and at least one chiral ligand selectedfrom the group consisting of a carboxylic acid-type ligand, anamide-type ligand, a phosphine-type ligand, an oxime-type ligand, asulfonic acid-type ligand, 1,3-diketone-type ligand, a Schiff base-typeligand, an oxazoline-type ligand, and a diamine-type ligand topreferentially produce a stereoisomer of the compound of the generalformula (I) wherein the stereochemical configuration at the 1-positionis S-configuration.
 2. The process according to claim 1 whichpreferentially produces a stereoisomer of a compound of the generalformula (I) wherein the stereochemical configuration at the 1-positionis S-configuration and the substituent represented by —COR and thefluorine atom is in cis-configuration.
 3. The process according to claim1 which preferentially produces a stereoisomer of a compound of thegeneral formula (I) wherein the stereochemical configuration at the1-position is S-configuration and the substituent represented by —CORand the fluorine atom is in trans-configuration.
 4. The processaccording to any one of claims 1 to 3 which is carried out in thepresence of said catalyst containing at least one chiral ligand selectedfrom the group consisting of a carboxylic acid-type ligand and anamide-type ligand.
 5. The process according to any one of claims 1 to 3which is carried out in the presence of a catalyst containing at leastone chiral ligand selected from the group consisting of a carboxylicacid-type ligand and an amide-type ligand together with at least oneligand selected from the group consisting of a halogen-type ligand, aphosphine-type ligand, an oxime-type ligand, a sulfonic acid-typeligand, a 1,3-diketone-type ligand, a Schiff base-type ligand, and acarbon monoxide type ligand.
 6. The process according to any one ofclaims 1 to 3 which is carried out in the presence of a catalystcontaining at least one chiral ligand selected from the group consistingof a carboxylic acid-type ligand and an amide-type ligand together withat least one ligand selected from the group consisting of a halogen-typeligand, a phosphine-type ligand, and a carbon monoxide type ligand. 7.The process according to any one of claims 4 to 6 which is carried outin the presence of the catalyst containing two or more identical chiralligands selected from the group consisting of a carboxylic acid-typeligand and an amide-type ligand.
 8. The process according to any one ofclaims 1 to 3 which is carried out in the presence of the catalystcontaining as ligands only identical chiral ligands selected from thegroup consisting of a carboxylic acid-type ligand and an amide-typeligand.
 9. The process according to any one of claims 4 to 6 which iscarried out in the presence of the catalyst containing at least onecarboxylic acid-type chiral ligand.
 10. The process according to any oneof claims 4 to 6 which is carried out in the presence of the catalystcontaining two or more identical carboxylic acid-type chiral ligands.11. The process according to any one of claims 1 to 3 which is carriedout in the presence of the catalyst containing as ligands only identicalcarboxylic acid-type chiral ligands.
 12. The process according to anyone of claims 4 to 6 which is carried out in the presence of thecatalyst containing at least one amide-type chiral ligand.
 13. Theprocess according to any one of claims 4 to 6 which is carried out inthe presence of the catalyst containing two or more identical amide-typechiral ligands.
 14. The process according to any one of claims 1 to 3which is carried out in the presence of the catalyst containing asligands only identical amide-type chiral ligands.
 15. The processaccording to any one of claims 1 to 14 which is carried out in thepresence of the catalyst containing cobalt, rhodium, iridium, ruthenium,palladium, molybdenum, copper, or iron as the metal atom.
 16. Theprocess according to any one of claims 1 to 14 which is carried out inthe presence of the catalyst containing rhodium as the metal atom. 17.The process according to any one of claims 1 to 3 which is carried outin the presence of the catalyst containing at least one chiral ligandselected from the group consisting of an oxazoline-type ligand and adiamine-type ligand.
 18. The process according to claim 17 which iscarried out in the presence of the catalyst containing copper as themetal atom.
 19. The process according to claim 18 wherein a coppersource is at least one substance selected from the group consisting ofcopper (I) trifluoromethanesulfonate [CuOSO₂CF₃] and copper (II)trifluoromethanesulfonate [Cu(OSO₂CF₃)₂].
 20. The process according toany one of claims 1 to 19 wherein X is chlorine atom or bromine atom.21. The process according to any one of claims 1 to 19 wherein R isC₁₋₁₀ alkyloxy group.
 22. The process according to any one of claims 1to 19 wherein R is ethoxy group.
 23. A process for preparing a(1S,2S)-2-fluorocyclopropanecarboxylic acid derivative, which comprisesthe steps of: (A) preparing a stereoisomer of the compound of thegeneral formula (I) according to the process of any one of claims 1 to22 ; and (B) subjecting the resulting stereoisomer to dehalogenation toreplace X of the stereoisomer with hydrogen atom to prepare a(1S,2S)-2-fluorocyclopropanecarboxylic acid derivative.
 24. A processfor preparing a (1S,2S)-2-fluorocyclopropanecarboxylic acid derivativewhich comprises the step of subjecting a stereoisomer of the compound ofthe general formula (I) prepared according to any one of the reactionprocesses defined by claims 1 to 22 to dehalogenation reaction withoutpurification or isolation to replace X of the stereoisomer with hydrogenatom to prepare a (1S,2S)-2-fluorocyclopropanecarboxylic acidderivative.